Nordesoxycorticosterone esters



Oct 30, 1951 M. R. EHRENSTEIN NoRDEsoxYcoRTIcosTERoNE EsTERs Filed May8, 1948 o /QI o Patented Oct. 30, 1951 Maximilian R. Ehrenstein,Philadelphia, Pa.as

signor to The Trustees of the UniversityV Aof Pennsylvania, Philadelp of-Pennsylvania ApplicatiggMay s, 1948,-seria1ivq. 25,824

This invention relates n compounds believed variously to havephysiological activity and variously to have value as intermediates andmethod for their production. s

More specically,'the new chemical compounds contemplated by thisinvention will include the new compound 10-nor-11-desoxycorticosteroneacetate and various intermediates, which are produced in the course ofits vpreparation by the method according to this invention.

The new compound, 10-nor-ll-desoxycorticosterone acetate, have beenfound to have physiological activity. The various other new compoundsand intermediates formed in the course of preparation thereof and oflO-nor-ll-desoxycorticosterone acetate and the corresponding alcoholwill nd utility as intermediates and will have physiological activity.

' The particular structure of the new compound,

V10-nor-11-desoxycorticosterone acetate, andthe structure of the novelcompounds comprising intermediates formed in the preparation of l0-nor-ll-desoxycorticosterone acetate, and the procedure according to themethod of thislin-'ven- The formulae illustrates the structures cf 1'10-norprogesterone and of the several intermediates formed in the course ofits preparation and the several steps of the method according to thisvention are broadly indicated.

In the scheme the starting material or compound is indicated at A.' Thismaterial, Ia saturated dicarboxylic acid having the formula CzoHaoOs(estrane-3,5diol-l0,17dicarboxylic acid), has heretofore been preparedand is described, for example, by Butenandt and Gallagher, Ber. 72, p.1866 (1939); Chem. Abst. 34, p. 773 .(1940).

Proceeding now according to the method of this invention, as indicatedin the scheme, the compound B is formed by acylation of the startingcompound A to protect the hydroxyl group at carbon atom 3. The acylationof the compound A is, for example, eiectedby treatment with an 1 acidanhydride, as, for example, acetic anhydride, propionic anhydride, orothersuitable anhydride which will protect the hydroxyl group at carbonatom 3. l

As exemplifying the procedure for acylation of Y the compound A, usingacetic anhydride, anhydride, a solution of 0.450 g. of recrystallizedestrane -3,5-diol-10,17dicarboxylic acid in 4.5 cc.

Vof acetic anhydride'isrrefluxed (metal-bath, 140- 150 C.) for 30minutesafter which-450e. of

to certain new chemical A glacial'acetic and cc. kof water areadded'itox decomposeianhydrides and the solutionthen heatedon a water bathfor about onehour; rOn

completion of the heating the solvent is removed Y .in vacuo. (50" C.)and. the sirupy'residue taken up in ether and thev solutionextracted'ltwicewith ice vcold dilute sodium fcarbonate.. i The combined.extracts arelacidied by adding' Without delay ice cold dilutehydrochloric acid whichwill cause a white occulent precipitate to.vappear.

' The suspension. is V thenY extracted three times with V.ether and thecombined 'ether extracts ``washed several 'times with smallquantitiesiof'waten After drying and filtering, evaporation ofthe ether-yieldsa-product. usually obtained as a foamy, colorless glass. This product,which Y.comprises the ycompound B, is then, for analysis,

in- Y avoid possible 20 dried at 85 C. under slight vacuum in order-.to

decomposition and analyzes asffollows; .A .p' .V 1.2,;

Calculated 'forel V(71221-13201 fi (monoacetate-)z '1'. 64.66; H, 7.90.Found: C, 64.20; H, 7.36.

Proceeding now from' the compound B to the compound C, which, foreintinplemmayv be 3- a'cetoxy 10 noretiocholenic acid(Seacetoxyestrene-l'Z-carboxylic acid), the compound Bljis subjected toheating in a highvacuum to effect dehydration andy decarboxylation ottheY `compound B.` Preferably the compound B Vw'illbe subjectedtofdistillation in a high vacuum. As exemplifyin'g the' procedure forthe preparation oi compound C from the compound B, `w h ere the compoundB is; for example', an acetate, 0 :590 g. of the crude compoundB is'transferredinto a high vacuum retort by means of ether. fAfter carefulremoval of the solvent, a foamyglassremains, which, on gentle heatinginahighvacuumto atemperature of 804120 C.,`is almost completelyliquefiedv or sintered. The material thus obtained; essentially free,',from solvent,v is

subjected'to distillation in a high vacuum. In effecting thedistillation the temperatureis raised fairly quickly to about-180?Cqwhere gas evolption will be observed? Subsequently, the'teniperatureis "rai'sed slowly, say within af period of "about onehounto 2501'C. andthen quickly-raised j tolabout 290 Gand the distillationthereafterinterrupted.v I he distillate, usually a'fsli'ghtly yelyssshows the following: 1

low,- brittle` glass; isjsub'jected another` distilla- "tion underpractically identicalconditionsjit being v noted -thatin vtheredistillationthere -is no vnotable-gas evolution; The product usuallyisfa y slightly yellow, brittle glassl'and gives'V a 'strong positivereaction with" tetranitromethane, Anal- In this product as illustratedin the scheme the doublefbondimaybein the@ 5,6 position, inrthe 5,10positionfzforrinifthe 4,5 positionfior theproduct may be a mixture ofany two or all of these isomers hereinafter indicated by referencesto`and/or isomers. However,..no attempt.. was made to separate theseisomers.

Proceeding now for the preparation' offthecompound D, which, forexarrple';.may"be4 S-aetoxy- -noretiocholenic acid chloride i(-3-.ac'setoiqr-L` estrene-l'I-carboxylic acid chloride) and/or isomers,the compound C is directly transformed into the corresponding acidchloride and/or isomers by means of, for example, thiony-l'3 chloride,phosphorous oxychloride or phosphorous penta- 2 chloride. elta-will .beunderstoodz thatrthe commay :be prepared 'asfan acid bromide :by.reusing an?4 equivalent bromide -infplace-ofv -thezafore- @mentionedchlorides.

cA's exemplifying the procedure forthe-preparationlof the compound. Dfrom-the' compound C, a Apuried; colorless-ifthionyl;chloride isiprepared, forflexample;;bydistillmgfpure commercial thionyl :bhloride-`(Eastman) yaoi. a' slightlyyellow color, ywerquinolinefand; thenfover.vlinseedmil. .To :f--200 mgwof xthefcompound C.= and/or..;isomers,fiswedded.y in: al-coldroom. 1.0" ccwof the -puried i-thionylchloridefzVf'Ihe-mixture. is'allowed. to stand under anhydrous.l conditions: linthe. fcold .room :.-Cabout 2.-C.) for a .period of about 50 minutesand.` then-at-froomitemperature C.)4 for about 13.1/1'f-hours; whichusuallyfresults inthe formation .fief-anoliveV green solution. f Thesolution..thus .Jformed is"y brought ,to'dryness-in .vacuo V(40" C.)

under anhydrous conditions. 'I'he residue is ther;4if-dried'szwernightfin a =`vacuum-:desiccator .'I'heaoidhloride, or thebromidejthus pre- .'pa-redserves for thepr'odction'dfthe compoundE,.as,`n for exaiii'ple 3-acetoxylO-norpregnenew20onefa"ndloii isomers.Y

The compound'lD, or -related compoundsindilcated above, 'and/or isomers,is` of value not only,

as an intermediate fortheprepati'oni`of the noifel compound"10-nor-.1ladesoxycoiticosterone .acetate according t`o` th`elrethodfofthis' invention, but .likewise is useful lfor" 'the preparation 'of the1 novel compound lO-norprogesterone.

` Proceeding no6/(flor .the'pieparationo'ftheoom- .pouhdEg or.' of` therelatedcompoundsf indicated .ilabove van'd/oirSisomers, inparticular`3-aoetoxy- AE"2ldiazo-l-norpregnenIZOone; ah'd/or` isomers.

'lthe compound`.D,.or` related compounds indicatedJY "above .and/orisomers; is subjected to` treatment f witldiazomethane.'

l-.As exemp'li'fyin'gv theprocedure furthe/.preparap @tion ofthe fcompound E fromthe compound' D, -i a. Isolation of diazomethaneinfvetl'ieris.4 prepared f ronr5l15l g. V'of'nitrosomathylurea.'v dried.Overpellets of pure potassium hydroxide and redistilled -underanhydrous conditions. To -45 cc. 'ofi this solutionr at a temperatureof.-55 C.r is then added '51 cc. vofan ethereal 'solutionof the. acidchloride .(compoundl D) :as lobtain'ed Yfrom 0.39.. off the compound C.(a'nd/orisomers). as described above. The. mixture;` usually. ofaifgc'Jlden-yellow..colori4 is llowed to lstand .in ahold room- (about.iii-2 C.) for" about 7 hours, and thenA atlroomftemper'ature.`(say,..30-33.-C.) for about twodays. Thereafter the mixtureisconcntrat'ed tovaboutonerthird. of its volumeon awatenbatmfiltelfedand brought to dryne'ssin` vacuoandthen further dried in a vacnum"dsiccator overnight. The products compound E, and/or isomers, is usuallyan amber Stcolored, viscous-material.

' slur-'I1 thehpreparationfnow of the-"compound F,21-diazo-10-norpregnene-20-one-3-ol, and/or iso- 5'f.mers, the compoundE is subjected to hydrolysis on the .alkaline side.

Asexemplifyin'gprocedure for the preparation Q.:offithe compound Eiiromthe compound E, to a aesolution off .52 gffof the compound E, asprepared loi'abovefinl29iccfof methanol, is added a solution of 0525`galof'epota'ssium hydroxide in 0.3 cc. of awater..,and 5.-.co. ofmethanol, and the mixture allowed` to stand at room temperature (say, 32Cfr-forfabout six hours. Then 0.53 g. of potassium 15 bicarbonatedissolved" in 20 ce. of Water is i.faddedito:thefsolutionsand .thesolution then iconzcentrated :to: a volume-y of-4 20...cc. inwacuo dsa?,r#145?, .C.). .TheeY concentrated; solution is.then'fex tracted- 4threetimes withfample quantitiesmf 2U l'ethery and the combined etherextractsare washed three times" vwith Water,= dried with sodiumv sulfate,1:..filtered;iand-:fbroughtsto: dryness. The residue.comprisingacompound; F is usually.: an g. amber :colored'ffoamy-fglassamounting-:to labout 0-.42g. 25 The compound-G,2lfdiazo-ID-norprogesterone 5(21@V -nfdiazo 10 -vnor -ix 4 fpregnene13,20- -fdione) is=;iornedr frormthe.- compound F fby'sub- .=ieci',ing.1:the compound F 'to `deny,drogenation As exemplfyi-ng the-procedurefor-the forma- 30. tion-.ofithe compound Gfrom,rthe compound F, asolution :of 0.85,V g. of `'aluminum tertfbutoxidelf(Eastma-n)..in-.35-. cc. rof-.drybenzeneis' separated by decantationfrom a trace of undissolved material. J'Iofthisjsolution isaddedarl-solution o1.' :.0;33 g. of-compoundE in10cc. of,dryacetone Themixture. is remixed-under anhydrous conditions on afwaterebath foraf-periodfof ten hours aduring `Whichftirne another Zocordry acetone isadded. .The mixturefis-allowedto stand at room 40 temperatureovernightand then a relatively large y amount offredistilled ether'isvadded andthe mix- A.,ture washed.twice vwithafsaturated solution of potassiumsodium.tartrateftwice',with a dilute solution of sodium carbonatetandthree times with Water. -gnfter drying .withv sodium. sulfateand-.1tering, thesolvent is removed in vvacuo '.(about 45C.).--'I'he^residue,usually an amber Acolored -viscous resin, :comprisesthe compound G in amount of about-0l35 g. 0 -Thecompound-H,..lO-nor-.llfdesoxycorticos- .terone acetatefisrformedfrom-thecornpound G.

Asfexemplifying..the-procedure--forthe formation of the compound H fromthe compound G, 0.35 g. of 21diazoe-lnorprogesterone is dis- 5 solved in5 cc. of anhydrous glacial acetic acid. The solution: is heatediat-about, 959. C.- for :about w15 .rnirn-ites;J thenrdurmgzrlzmore.minutes;;the e temperatureisxaisedsto about-1204125?. C. where itiisrkeptforf: cminutes. .Thereaiten thesa'cetic facidfisfremovedrin`'vacuo #(aboutfSO? C.)f. andthe vresidue obtained is takengup in .alargezamountof ether and,-the.solution.-iiltered. The ether-.phase Y -isWashedswith a'solution; of Nt vsodium-,bicar-.-bonatevand:three(timesiwitlrwvater. fThen-,jafter 65.*dryingWith-.sodiuma' sulfate :and -ltering;f the xether isiremovedrinfvacuo.The, residue,l amountginge itc-abouti .0.;2Z'f gs; is' usually a 1 light.brown 'rresinfandfcomprising; the crudev compound; Hiis purified bychromatographic adsorptions.

:For-*fthe -fchrornotographic Aadsorptionmof the crude zmaterialf;0.27@4 g.-of.rthe1 materialhisfdisnsolved'iini--v-20 -cc; of benzeneandfloccl of 'petroflcum ether. and .-:theasolution .'-filtered througha Y -`column: -of 1,11 g. .'of-v-ai'uminum oxide aluminum 75,.-oxide.;anhydrous;4 e'zstandardizedifori;V chromatographic adsorption accordingto Brockmann E. Merck, Darmstadt). The original solution is passedthrough within two hours and the folsolution being passed through withinabout one hour and the following eluates within 15 to 20 minutes each,with the following results:

chromatographic fractionation II No of Weight of Fraction Solvent ARigue, Appearance of Residue 5 cc. benzene+20 cc. petr. ether 13. 4colorless oil.

(original solution). 5 cc. benzene+l5 cc. petr. ether- 9. 6 Do. 5 ce.benzene-H0 ce. petr. athen... 4. 9 colorless grease. 7.5 cc. benzene-H5cc. petr. ether. 3. 2 Do. 7.5 co. benzene-H5 cc. petr. ether. 2. 5 Do.yl0 cc. benzene+5 cc. petr. ether... 2. 8 colorless resin. l 12 ce.benzene-l-B cc. petr. ether.-- 2. 7 o. 14 cc. benzene-H cc. petr.ether... l. 6 Do. 15 cc. benzene 0. 9 Do. do.v 0. 8 colorless residue.

10 cc. benzene-lcc. ether. 1` 1 Do. 30 cc. ether 4. 3 slightly yellowoil. 12 cc. ether-l-B cc. methanol 1. 8 whitish resin.

15 ec. methanol 4. 4 whitish yellow residue.

Total 54. 0

lowing eluates within 25 and 30 minutes each. The chromatographicfractionation is as follows:

chromatographic fractionation I Further fractions 7-12 of the firstchromatogram combined (54.3 mg.) are subjected to re- N 0f vriegililt ofA fR id esi ue, ppearance o es ue Fraction Solvent mg cc` benzene-H0 cc.petr. ether 21. 4 slightly yellow oil.

(original solution).

20 cc. benzene-l-lO cc. petr. ether. 34. 6 yellow oil. cc. benzene-lcc.petr.y ether. 23. 6 slightly yellow resin. 28 cc. benzene+2 cc. petr.ether. 16. 4 Do. 30 cc. benzene 8.5 Do.

.-- o 5. 7 Do.

25 ce. benzene-F5 cc. ether 23. 7 yellow resin. 20 cc. benzene-H0 cc.ether 18.3 Do. l5 cc. benzene-H5 cc. ether. 8. 5 Do. 10 cc. benzene-H0cc. ether, 2.0 colorless resin. 5 cc. benzene-l-25 cc. ether.. 1. 1 Do.30 cc. ether 1. 6 Do.

do 12.8 yellow oil.

25 cc. ether-l-5 cc. chloroform.. 0.3 colorless residue. 15 cc.ether-|-15 cc. chloroform- 0. 8 Do. 30 cc. chloroform 7. 2 yellow resin.

25 cc. chloroform-lcc. methano 34. 6 whitish-brownish.

30 cc. methanol 13. l Do.

Total 234. 2

It is believed that the compound H, 10-nor-1ldesoxycorticosteroneacetate is present particularly in fractions 3-6, and in agreement withthis assumption it was found that these fractions give a positivereaction with silver diammine.

In order to secure a further quantity of the compound H, the fractions 1and 2 above comchromatographic adsorption by filtering a solutionthereof in 14 cc. of benzene and 6 cc. of petroleum ether through acolumn of 3 g. of aluminum oxide (Brockmann). The solution 5o passedthrough within about two hours and the eluates within 15 to 20 minuteseach, with the following results:

Chromatographic fractionation III No of Weight of Frac'on SolventResidue, Appearance of Residue nig.

14 cc. benzene-Hi cc. petr. ether 1.1 colorless residue.

(original solution).

14 ce. benzene-lcc. petr. ether.. 0.8 Do.

12 cc. benzene+3 cc. petr. ether. 1. 2 Do.

14 cc. benzene-i-l cc. petr. ether. 2. 8 colorless resin. 15 cc. benzene3. 5 Do.

` .do 3. 0 Do.

11 cc. benzene-F4 cc. ether.. 8. 5 pale yellow resin.

7 cc. benzene-F8 cc. ether.-. 3. 4 Do.

5 cc benzene+l0 cc ether.. 2.0 colorless resin. 30 cc. ether 4. 5 Do.7.5 cc. ether+7.5 cc. chloroform. 1. 6 Do. 15 cc. chloroform 4. O yellowresin. 12 cc. chloroorm-I-3 cc. methanol. l0. 0 whitish-yellow resin. 15cc. methanol 4. 7 whitish residue.

Total 5l. 1

bined (56.0 mg.) are subjected to rechromatographic adsorption insolution in a mixture of 5 cc. of benzene and 20 cc. of petroleum ether.The solution is filtered through a column of 3 g. of aluminum oxide(Brockmann), the original Finally, fractions 3-6 from the firstchromatogram, fractions 4-9 of the second chromatogram and fractions 1-6from the third chromatogram combined (75.5 mg.) are subjected tochromatographic adsorption in solution in a mixture of 15 cc. of benzeneand 15 cc. of petroleum ether. The solution is filtered through a columnof 3.7 g. of aluminum` oxide. (Brockmann) the original solu.- tion beingpassed through within .one hour and the eluates each within 20-25minutes, with the following results:

chromatographic fractionation IV No of Weightrof Y, A R Fraction Smm#Rlgs Premsa@ of residue 15 cc. benzene+15 cc. petr. ether. 1. 9Vcolorless grease. (original solution). 10 cel benzene-HO ce. petr.ether. 10.9 -colorless sticky resin. 12 cc. benzene-i-S cc. petr. ether5. 4 colorless solidfresin. Y 14 oc. benzene-Hi cc. petr. ether- 6.0 Do.16 ce. bonzene--4 ce. petr. ether. 5. 'r' Do. 18 cc. benzene-i-Z cc.petr. ether 4. 5 Do, 20 cc. benzene 3. 5 Do. do 2.4 Do. do 1. 5 Do.' 16cc. benzene+4 cc. ethe 2. 8 Do. l2 cc. beuzene+8 ce. ether. 1.8 Do. 8ec. benzene-H2 cc. ether 0. 9 Do. 2U oc. ether 1. 6 Do. o 1. 6 Do.

cc. ether-F5 ce. methanol 11.5 yellowish solid resinl cc. methanol 7. 4yellowish whitish glass.

Total 69. 4

Fractions 2-9 combined (39.9 mg.) from the chromatographic fractionationIV are subjected to distillation in a high vacuum. In effecting thedistillation the oven is heated within 15 minntes to 170 C., is raisedwithin 10 minutes to 230 C., and then within minutes more to 250 C. Thedistillate, usually a light yellow, very viscous resin, comprises thecompound H.

A solution of the product comprising compound H in methanol was found toreduce an alkaline solution of silver diammine after short standing atroom temperature and analyses as follows:

Calculated for C22Hso04: Found: C, '73.93; H, 8.30.

The compound is further characterized by its ultra-violet absorptionspectrum:

imax=23a 1m.; 6:14720 the compound H, but, to the contrary, contem-vplates the various compounds having the structure of compound H exceptfor the `fact that they will have the grouping COCH2Y at carbon atom 17,where Y is a halogen group or an acyloxy.

group of 2-6 carbon atoms. The compounds having the grouping COCHQY atcarbon atom 1'7 will,l

be prepared from `compound G as describedabove fforthe preparation oicompound H by use of the acid corresponding to the compound desired.

As specically illustrative of the seyeral compounds contemplated by thisinventionwhere Y is an acyloxy group ,of 2-6 carbonatoms, in addition tothe acetate heretofore described, `the propionate, .the butyrate, thevalerate and the caproate are specific examples.

y The ,structure of the severalcompoundswhere made completely apparentand the structure of the several compounds will be specicallyillustrated by the substitution for Y in compound H of a propionicgroup, a .butyric groupa valerio group and a caproic group,respectively.

The severalcompounds above specically men:

' tionedand specifically exemplified in the scheme will be, prepared asheretofore described in con-u nection with the v preparation of 10-nor11de soxycorticosterone*acetate by the useA of pro,- pion-ic, butyric,vvalericor caproic acid in place of acetic acid, with the productionrespectively of 10norv1l-desoxycorticosterone propionate, 10-nor-llTdesoxycorticosterone butyrate, 10-nor, ll-desoxycorticosteronevalerate and 10-nor-11- desoxycorticostero-ne caproate.

It will be understood, with reference to the several Acompoundsillustrated and described above, that I do not intend that thisinvention or the claims appended hereto shall be limited to anyparticular conguration about any carbon atom and,.in particular, aboutcarbon atoms 3, 10, 14 and 1.7.

This application is a continuation-in-part of an application led by meon March 24, 1945, Serial No. 584,624, now abandoned.

What I claim and desire to protect by Letters Patent is:

1. A compound having the following structure:

Where Y is anacyloxygroup selected from the group consisting 0funsubstituted aliphatic acyl- 0XX..g1Ql1P.S. Of ,2f- .Galbon .@OULS..

2. A compound having the structurez.

CHI

COCHOCOCHl 3. A compound having the structure:

C OCHxOC OCHICH:

4. A compound having thc structure:

C OCHQOC OCHICHICHI C OCHIO C OCHICHICHaCH;A

6. A compound having the structure:

OH: C 0 CHIO C O CHgCHzCHICHgCHl MAXIMILIAN R. EHRENSTEIN.

No references cited.

1. A COMPOUND HAVING THE FOLLOWING STRUCTURE